The ubiquitin-proteasome system (UPS) plays an important role in the conjugation pathway, which appends ubiquitin to the substrate proteins targeted for regulated degradation (Hershko, A. Cell Death Differ. 2005, 12, 1191-1197). Such ubiquitinylation pathway is composed of three enzymatic steps comprising ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) (UBC) and ubiquitin-protein isopeptide ligase (E3) (Hershko, A. et al., Annu. Rev. Biochem. 1998, 67, 425-479). Another pathway similar to the ubiquitinylation pathway that employs the ubiquitin-like protein NEDD8 (neural precursor cell-expressed developmentally down-regulated 8) has also been identified (Kerscher, O. et al., Annu. Rev. Cell Dev. Biol. 2006, 22, 159-180; Gong, L. et al., J. Biol. Chem. 1999, 274, 12036-12042). In the first step, NEDD8 is activated by E1 enzyme (NEDD8 activating enzyme, NAE). In the second step, NEDD8 is transferred to E2 enzyme (UBC12). Subsequently, E2 is conjugated to the substrate protein targeted for degradation. In this pathway, NAE plays an essential role in regulating the activity of a cullin-RING subtype (really interesting new gene) of ubiquitin ligases, whose substrates play important roles in the cellular processes associated with cancer cell growth (Pan, Z. Q. et al., Oncogene 2004, 23, 1985-1997). Therefore, NAE has been contemplated as a new target for the development of novel anticancer agents.
MLN4924 is a potent and selective inhibitor of NEDD8 activating enzyme (NAE) and is currently being investigated in phase I clinical trials as an anticancer agent for both solid tumor and hematological malignancies. MLN4924 mimics adenosine 5′-monophosphate (AMP), which is a tight binding product of NAE reaction (Haas, A. L. et al., J. Biol. Chem. 1982, 257, 10329-10337; Bohnsack, R. N. et al., J. Biol. Chem. 2003, 278, 26823-26830). MLN4924 inhibits the NAE pathway in cells, which results in S-phase defect, DNA damage and apoptosis (Soucy, T. A. et al., Nature 2009, 458, 732-737). MLN4924 also inhibits NAE pathway to induce DNA damage in mouse bearing human HCT-116 tumor xenografts (Soucy, T. A. et al., Nature 2009, 458, 732-737).
However, despite its potent anticancer activity MLN4924 has been little studied with regard to the method for synthesis thereof. Therefore, in consideration of the importance of said compound it is very important to develop the method for stereoselectively and efficiently synthesizing MLN4924 with a good overall yield under mild conditions.
Thus, the present inventors have studied under taking the above-mentioned aspects into consideration, and found that MLN4924 can be efficiently and stereoselectively prepared by means of key steps involving stereoselective reduction of cyclopentenone with isopropylidene, regioselective cleavage of isopropylidene moiety, and synthesis of cyclic sulfate, resulting in the completion of the present invention.